1、T细胞活化机制 Nave T cells Mature T cells that have not previously encountered antigen; Preferential migration to secondary lymphoid organs (lymph nodes), where they recognize antigen Effector T cells Activated T cells capable of performing the functions required to eliminate foreign antigens Preferential
2、 migration to sites of infection or inflammation Short-lived Memory T cells Long-lived, functionally silent cells; Mount rapid secondary immune responses to the same antigen exposure Heterogenous (central and effector) Based on the history of antigen encounter and the stage of T cell activation. 应答诱
3、导 外周淋巴器官内 抗原识别 T细胞扩增和分化 分化的细胞 进入循环 效应 T细胞和其他白细 胞迁移到感染部位 在 外周 效应 T细胞 遭遇抗原 效应 T细胞活化 T细胞的效应功能 . Activation of T cells changes the expression of several cell-surface molecules Functional responses of T cells Secretion of cytokines Proliferation Differentiation into effector T cells Differentiation into
4、memory T cells Secretion of cytokines One of the earliest detectable responses of T cells to antigen recognition Principle cytokine: IL-2 Distinct sets of cytokines secreted by effector T cells Clonal expansion of T cells Antigen-presenting cells are required for T cell activation Specific antigen r
5、ecognition by the T cells; Stable adhesion of the T cells to the APCs; Transduction of activating signals to the T cells. The initiation of T cell responses to specific antigen requires Each of these events is mediated by distinct sets of molecules on the T cells. T cell receptors and accessory mole
6、cules T cell receptor (TCR) The definitive T cell lineage marker Recognition of MHC-associated peptide antigen Dual specificity MHC restriction Antigen specificity No signal-transducing functions TCR complex Composed of TCR and CD3 protein invariant protein, identical in all T cells regardless of sp
7、ecificity responsible for signaling, but not antigen recognition Immunoreceptor tyrosine-based activation motif （ ITAM) CD3 Contains two copies of a conserved sequence: tyrosine-X-X-leucine/isoleucine Important for signal transduction in T cells Antigen recognition and signaling functions of T cells
8、 Antigen recognition Signaling functions Co-receptors CD4 and CD8 Mature T cells express either CD4 or CD8, but not both Involved in MHC-restricted T cell activation CD4 Class MHC molecules CD8 Class MHC molecules A category of membrane proteins that enhance TCR signaling through simultaneous bindin
9、g of the MHC molecules Two-signal Hypothesis Signal 1 TCR - MHC+Ag interaction not enough for full activation Overview of TCR signalling Nature Review Immunol 2013 three major signalling pathways Provided by Costimulatory Molecules on activated APCs APC T Cell B7 CD28 Signal 2 B7.1 (CD80) B7.2 (CD86
10、) promote the survival and expansion of the T cells A comparison between signalling pathways in fully stimulated and in anergized T cells defects at various points in the MAPK (mitogen-activated protein kinase) pathway downstream of co-stimulation Fathman and Lineberry, 2007, Nature Immunology Funct
11、ions of co-stimulators in T cell activation Cyclosporin A FK506 Rapamycin High-affinity IL-2 receptors are three-chain structures that are present only on activated T cells Mediated primarily by an autocrine growth pathway Proliferation Clonal expansion The frequency of nave T cells specific for a g
12、iven antigen is 1:105-6 Ag-specific CD8+ T cells 1:10 Ag-specific CD4+ T cells 1:100/1000 Ag-specific memory T cells 1:104 Ag is eliminated Phases of T cell responses priming Variation in signal 3 causes naive CD4 T cells to acquire several distinct types of effector functions A model for the regulation of early TH2 differentiation by TCR signal strength Hidehiro Yamane & William E Paul, 2012 Nature Immunology A model for early determination of iTreg fate versus TH17 fate controlled by TCR signal strength Hidehiro Yamane & William E Paul, 2012 Nature Immunology
